Endogenous adenosine depresses synaptic transmission in rat hippocampal slices during periods of hypoxia, a potentially neuroprotective cellular response that is attenuated by the adenosine antagonist 8-cyclopentyltheophylline. In this study, rats were exposed to moderate hypoxic conditions (5% O2- 95% N2, 40 min x three days) in the presence or absence of 8-cyclopentyltheophylline, and the effects of reducing adenosinergic inhibition during hypoxia were assessed histologically and behaviorally. Half the rats exposed to low levels of oxygen in the presence of 8-cyclopentyltheophylline (10 mg/kg) suffered unilateral or bilateral hippocampal damage largely limited to the CA1 subfield. Animals which had suffered hippocampal damage were also impaired in their performance of a working memory version of the Morris Water Maze, but not a passive avoidance task (step-through). Hypoxia alone did not result in neuronal damage or behavioral impairment. These results provide further evidence that endogenous adenosine provides an important level of neuronal protection during even prolonged periods of hypoxia.